Host–guest chemistry

a) Structure of 18-crown-6. b) Threading of crown ether and 1,2,3-triazole (rotaxane). Redrawn from [3]. c) Inclusion of a-CD and polyethylene glycol (PEG) d) Threading of b-cyclodextrin and thiophene-based molecule. Redrawn from.[8]

Crown ethers are ring-like structures composed of several units of ethylene glycol. Because the radius of their pores are similar to that of alkali metal ions, crown ethers are well known for their ability to bind metallic ions. For example, 12-crown-4, 15-crown-5, 18-crown-6, 21-crown-7, and 24-crown-8 interact with potassium, sodium, ammonium, and calcium ions, respectively.[8] Among the aforementioned crown ethers, all the ions have the strongest binding affinity with 18-crown-6 because the size of 18-crown-6 most closely matches that of the ions. Besides ionic species, crown ethers can also bind to neutral molecules, e.g., 1, 2, 3- triazole. Crown ethers can also be threaded with long, linear molecules and/or polymers, giving rise to supramolecular structures called rotaxanes. Given that the crown ethers are not bound to the chains, they can move up and down the threading molecule.[11]

Cyclodextrin (CD) is composed of several glucose units and connects by ether bonds. There are three kinds of CDs, α-CD (6 units), β-CD (7 units), and γ-CD (8 units). The heights of the structure are all around 8 Å, while the cavity sizes of them are different, around 5, 6, and 8 Å, respectively. By comparing the size of the guest molecule and the CD, the binding behavior can be predicted. For instance, if the guest molecule is larger than the CD, it can be assumed that the binding will not occur. Typically, the α-CD can thread onto one PEG chain, while γ-CD can thread onto 2 PEG chains. β-CD can bind with thiophene-based molecule.[8]

a) Structure of Cryptophanes. b) Structure of Resorcinarenes and Pyrogallolarenes. c) Structure of cucurbit[n]urils. Redrawn from.[8]

The structure of cryptophanes contain 6 phenyl rings, mainly connected in 4 ways . Due to the phenyl groups and aliphatic chains, the cages inside cryptophanes are highly hydrophobic, suggesting the capability of capturing non-polar molecules. Based on this, cryptophanes can be employed to capture xenon in aqueous solution, which could be helpful in biological studies.[8]

One of the classic structures of resorcinarenes and pyrogallolarenes is shown below. Because of the phenol group, some hydrogen bonds are foromed among the molecules. Sometimes, the binding ratio of the host and guest could reach 2 : 1.[8]

Cucurbit[n]urils have similar size of γ-CD, which also behave similarly (e.g., 1 cucurbit[n]uril can thread onto 2 PEG chains).[8]

When the host and guest molecules combine to form a single complex, the equilibrium is represented as

${\displaystyle H+G\leftrightharpoons HG}$

and the equilibrium constant, K, is defined as

${\displaystyle K={\frac {[HG]}{[H][G]}}}$

where [X] denotes the concentration of a chemical species X (all activity coefficients are assumed to have a numerical values of 1). The mass-balance equations, at any data point,

${\displaystyle T_{H}=[H]+K[H][G]}$

${\displaystyle T_{G}=[G]+K[H][G]}$

where ${\displaystyle T_{G}}$ and ${\displaystyle T_{H}}$ represent the total concentrations, of host and guest, can be reduced to a single quadratic equation in, say, [G] and so can be solved analytically for any given value of K. The concentrations [H] and [HG] can then derived.

${\displaystyle [H]=T_{H}-T_{G}+[G]}$

${\displaystyle [HG]=K[H][G]}$

The next step in the calculation is to calculate the value, ${\displaystyle X_{i}^{calc}}$, of a quantity corresponding to the quantity observed ${\displaystyle X_{i}^{obs}}$. Then, a sum of squares, U, over all data points, np, can be defined as

${\displaystyle U=\sum _{i=1,np}(X_{i}^{obs}-X_{i}^{calc})^{2}}$

and this can be minimized with respect to the stability constant value, K, and a parameter such the chemical shift of the species HG (nmr data) or its molar absorbency (uv/vis data). The minimization can be performed in a spreadsheet application such as EXCEL by using the in-built SOLVER utility.

This procedure is applicable to 1:1 adducts.

Set of NMR spectra from a host–guest titration

With nuclear magnetic resonance (NMR) spectra the observed chemical shift value, δ, arising from a given atom contained in a reagent molecule and one or more complexes of that reagent, will be the concentration-weighted average of all shifts of those chemical species. Chemical exchange is assumed to be rapid on the NMR time-scale. terms of mole fractions,

${\displaystyle {\bar {\delta }}=\sum x_{i}\delta _{i}}$

${\displaystyle \delta _{i}}$ is the chemical shift of the ith chemical species which contains the nucleus and ${\displaystyle x_{i}}$ is the concentration /mole fraction (${\displaystyle x_{i}={\frac {c_{i}}{\sum _{j}c_{j}}}}$ c is a concentration / mol dm⁻³) of that species. This expression has the same mathematical form as Beer's law. Chemical shift values may be obtained for more than one nucleus in an analogous way that absorbance may be measured at more than one wavelength. Typical isotopes that may be used in this context are ¹H,¹³C and ³¹P. It is usual to use a deuterated solvent when measuring ¹H chemical shift values.

Typical ultraviolet–visible spectra for a host–guest system

It is assumed that the absorbance of each species is proportional to the concentration of that species, according to the Beer–Lambert law.

${\displaystyle A_{\lambda }=\ell \sum _{i=1}^{N}\varepsilon _{i,\lambda }c_{i}}$

where λ is a wavelength, ${\displaystyle \ell }$ is the optical path length of the cuvette which contains the solution of the N compounds (chromophores), ${\displaystyle \varepsilon _{i,\lambda }}$ is the molar absorbance (also known as the extinction coefficient) of the ith chemical species at the wavelength λ, c_i is its concentration. When the concentrations have been calculated as above and absorbance has been measured for samples with various concentrations of host and guest, the Beer–Lambert law provides a set of equations, at a given wavelength, that which can be solved by a linear least-squares process for the unknown extinction coefficient values at that wavelength.

The treatment of this type of data is similar to the treatment of absorbance data. In fact the equation defining the relation between fluorescent intensity and species' concentrations is very similar.

${\displaystyle I_{\lambda }=\sum _{i=1}^{N}\varphi _{i,\lambda }c_{i}}$

where ${\displaystyle \varphi _{i,\lambda }}$ is the fluorescent intensity of the ith species at unit concentration.

The heat evolved when an aliquot of host solution is added to a solution containing the guest is the sum of contributions from each reaction

${\displaystyle Q_{j}=\sum _{i=1}^{N}\Delta H_{i}^{\ominus }\times \delta n_{i,j}}$

where ${\displaystyle Q_{j}}$ is a measured heat change value (corrected for all extraneous heat contributions) at data point j, ${\displaystyle \Delta H_{i}^{\ominus }}$ is the amount of heat absorbed or emitted when 1 mole of the ith reaction product is formed and ${\displaystyle \delta n_{i,j}}$ is the actual change in the number of moles of that product at that data point.${\displaystyle \delta n}$ is calculated by solving the equations of mass-balance with given values of the equilibrium constants. If the equilibrium constant values are known, the standard enthalpy change may be calculated by a linear least-squares process, otherwise a non-linear method of data-fitting must be used.

Isothermal titration calorimetry is commonly used to determine the values of both an equilibrium constant and the corresponding standard reaction enthalpy. The manufactures of ITC instruments supply some software with which these quantities may be obtained from experimental data values.

For each equilibrium involving a host, H, and a guest G

${\displaystyle pH+qG\leftrightharpoons H_{p}G_{q}}$

the equilibrium constant, ${\displaystyle \beta _{pq}}$, is defined as

${\displaystyle \beta _{pq}={\frac {[H_{p}G_{q}]}{[H]^{p}[G]^{q}}}}$

The values of the free concentrations, ${\displaystyle [H]}$ and ${\displaystyle [G]}$ are obtained by solving the equations of mass balance with known or estimated values for the stability constants.

${\displaystyle T_{H}=[H]+\sum p\beta _{pq}[H]^{p}[G]^{q}}$

${\displaystyle T_{G}=[G]+\sum q\beta _{pq}[H]^{p}[G]^{q}}$

Then, the concentrations of each complex species may also be calculated as ${\displaystyle [H_{p}G_{q}]=\beta _{pq}[H]^{p}[G]^{q}}$. The relationship between a species' concentration and the measured quantity is specific for the measurement technique, as indicated in each section above. Using this relationship, the set of parameters, the stability constant values and values of properties such as molar absorptivity or specified chemical shifts, may be refined by a non-linear least-squares refinement process. For a more detailed exposition of the theory see Determination of equilibrium constants. Some dedicated computer programs are listed at Implementations.

The binding process is reversible, indicating that the associate constant (k_a) is not far larger than disassociate constant (k_d). Combing the rate of the reaction, k_a, k_d, concentration, and time, the relation of the free guest molecule and time can be calculated.[14] By calculating the integration of UV spectrum or NMR,[15][14] the concentration as a function of time curve can be obtained.

Self-healing mechanism of host-guest interaction by a) using host-small guest molecule and b) host-polymer. Redrawn from [20][21]

Because of the non-covalent host-guest interaction, the polymer backbone can have enough flexibility to diffuse. If a crack exists in the materials, after compressing the two materials around the crack, because of the fast exchange of the host-guest molecular structure, the crack will rejoin again revealing good self-healing properties. Harada et al reported a self-healing hydrogel constructed by vinyl-group-modified cyclodextrin and adamantane.[20][22] Another strategy is to use the interaction between the polymer backbone and host molecule (host molecule threading onto the polymer). If the threading process is fast enough, self-healing can also be achieved.[21]

Generally, it is not easy to achieve pure organic phosphorescence, partly because of the instability of the triplet state (easily be quenched by moisture, oxygen, etc). Host-guest structures can provide a rigid matrix, which protects the triplet state from being quenched. In this circumstance, α-CD and CB could be used,[23][24] in which the phosphor is served as a guest to interact with the host. For example, 4-phenylpyridium derivatives interacted with CB, and copolymerize with acrylamide. The resulting polymer yielded ~2 s of phosphorescence lifetime. Additionally, Zhu et al used crown ether and potassium ion to modify the polymer, and enhance the emission of phosphorescence.[25]

Some guest molecules are charged compounds, which might be oxidized or reduced by certain chemicals. This type of guest molecule can present redox responsiveness. Some host molecules (i.e., α-CD) or guest molecules (i.e., tetra ammonium ion) are pH-sensitive, different pH can result in different species, which significantly influences the binding behavior, giving the material pH responsive properties. Some guest molecules may change their configurations under different lights, which makes the material photo-responsive.[26] Cai et al employed a halogen bond to prepare a host-guest system, and the materials are heat- and mechano-responsive with long persistent emission.[27]

An encryption system constructed by pillar[5]arene, spiropyran and pentanenitrile (free state and grafted to polymer) was constructed by Wang et al. After UV irradiation, spiropyran would transform into merocyanine. When the visible light is was shined on the material, the merocyanine close to the pillar[5]arene-free pentanenitrile complex had faster transformation to spiropyran; on the contrary, the one close to pillar[5]arene-grafted pentanenitrile complex has much slower transformation rate. This spiropyran-merocyanine transformation can be used for message encryption.[28] Another strategy is based on the metallacages and polycyclic aromatic hydrocarbons.[29] Because of the fluorescnece emission differences between the complex and the cages, the information could be encrypted.

Although some host-guest interactions are not strong, increasing the amount of the host-guest interaction can improve the mechanical properties of the materials. As an example, threading the host molecules onto the polymer is one of the commonly used strategies for increasing the mechanical properties of the polymer. It takes time for the host molecules to de-thread from the polymer, which can be a way of energy dissipation.[22][30][31] Another method is to use the slow exchange host-guest interaction. Though the slow exchange improves the mechanical properties, simultaneously, self-healing properties will be sacrificed.[32]

Traditionally, chemical sensing has been approached with a system that contains a covalently bound indicator to a receptor though a linker. Once the analyte binds, the indicator changes color or fluoresces. This technique is called the indicator-spacer-receptor approach (ISR).[33] In contrast to ISR, indicator-displacement assay (IDA) utilizes a non-covalent interaction between a receptor (the host), indicator, and an analyte (the guest). Similar to ISR, IDA also utilizes colorimetric (C-IDA) and fluorescence (F-IDA) indicators. In an IDA assay, a receptor is incubated with the indicator. When the analyte is added to the mixture, the indicator is released to the environment. Once the indicator is released it either changes color (C-IDA) or fluoresces (F-IDA).[34]

Types of Chemosensors. (1.) Indicator-spacer-receptor (ISR) (2.) Indicator-Displacement Assay (IDA)

IDA offers several advantages versus the traditional ISR chemical sensing approach. First, it does not require the indicator to be covalently bound to the receptor. Secondly, since there is no covalent bond, various indicators can be used with the same receptor. Lastly, the media in which the assay may be used is diverse.[35]

Indicator-Displacement Assay Indicators. (1.) Azure A (2.) thiazole orange

Chemical sensing techniques such as C-IDA have biological implications. For example, protamine is a coagulant that is routinely administered after cardiopulmonary surgery that counter acts the anti-coagulant activity of herapin. In order to quantify the protamine in plasma samples, a colorimetric displacement assay is used. Azure A dye is blue when it is unbound, but when it is bound to herapin, it shows a purple color. The binding between Azure A and heparin is weak and reversible. This allows protamine to displace Azure A. Once the dye is liberated it displays a purple color. The degree to which the dye is displaced is proportional to the amount of protamine in the plasma.[36]

F-IDA has been used by Kwalczykowski and co-workers to monitor the activities of helicase in E.coli. In this study they used thiazole orange as the indicator. The helicase unwinds the dsDNA to make ssDNA. The fluorescence intensity of thiazole orange has a greater affinity for dsDNA than ssDNA and its fluorescence intensity increases when it is bound to dsDNA than when it is unbound.[37][38]

A crystalline solid has been traditionally viewed as a static entity where the movements of its atomic components are limited to its vibrational equilibrium. As seen by the transformation of graphite to diamond, solid to solid transformation can occur under physical or chemical pressure. It has been proposed that the transformation from one crystal arrangement to another occurs in a cooperative manner.[39][40] Most of these studies have been focused in studying an organic or metal-organic framework.[41][42] In addition to studies of macromolecular crystalline transformation, there are also studies of single-crystal molecules that can change their conformation in the presence of organic solvents. An organometallic complex has been shown to morph into various orientations depending on whether it is exposed to solvent vapors or not.[43]

Host guest systems have been utilized to remove hazardous materials from the environment. They can be made in different sizes and different shapes to trap a variety of chemical guests. One application is the ability of p-tert-butycalix[4]arene to trap a cesium ion. Cesium-137 is radioactive and there is a need to remove it from nuclear waste in an efficient manner. Host–guest chemistry has also been used to remove carcinogenic aromatic amines, and their N-nitroso derivatives from water. These waste materials are used in many industrial processes and found in a variety of products such as: pesticides, drugs, and cosmetics.[44][45]